Langmans embryology, 9th ed

c h a p t e r 1Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes Primordial Germ Cells Development begins with fertilization, the pro-cess by which the male gamete, th

First Week of Development: Ovulation to Implantation 31chapter 3

Second Week of Development: Bilaminar Germ Disc 51chapter 4

Third Week of Development: Trilaminar Germ Disc 65chapter 5

Third to Eighth Week: The Embryonic Period 87chapter 6

Third Month to Birth: The Fetus and Placenta 117chapter 7

Birth Defects and Prenatal Diagnosis 149

x Contents

chapter 9

Muscular System 199

chapter 10 Body Cavities 211

chapter 11 Cardiovascular System 223

chapter 12 Respiratory System 275

chapter 13 Digestive System 285

chapter 14 Urogenital System 321

chapter 15 Head and Neck 363

chapter 16 Ear 403

chapter 17 Eye 415

chapter 18 Integumentary System 427

chapter 19 Central Nervous System 433

part three Appendix . 483

Answers to Problems 485

Figure Credits 499

Index 507

The ninth edition of Langman’s Medical Embryology adheres to the tradition

established by the original publication—it provides a concise but thorough scription of embryology and its clinical significance, an awareness of which isessential in the diagnosis and prevention of birth defects Recent advances in ge-netics, developmental biology, maternal-fetal medicine, and public health havesignificantly increased our knowledge of embryology and its relevance Becausebirth defects are the leading cause of infant mortality and a major contributor todisabilities, and because new prevention strategies have been developed, under-standing the principles of embryology is important for health care professionals

de-To accomplish its goal, Langman’s Medical Embryology retains its unique

ap-proach of combining an economy of text with excellent diagrams and scanningelectron micrographs It reinforces basic embryologic concepts by providingnumerous clinical examples that result from abnormalities in developmentalprocesses The following pedagogic features and updates in the ninth editionhelp facilitate student learning:

Organization of Material: Langman’s Medical Embryology is organized into two

parts The first provides an overview of early development from gametogenesisthrough the embryonic period; also included in this section are chapters onplacental and fetal development and prenatal diagnosis and birth defects Thesecond part of the text provides a description of the fundamental processes ofembryogenesis for each organ system

Molecular Biology: New information is provided about the molecular basis of

normal and abnormal development

Extensive Art Program: This edition features almost 400 illustrations,

includ-ing new 4-color line drawinclud-ings, scanninclud-ing electron micrographs, and ultrasoundimages

Clinical Correlates: In addition to describing normal events, each chapter

con-tains clinical correlates that appear in highlighted boxes This material is signed to provide information about birth defects and other clinical entities thatare directly related to embryologic concepts

de-vii

viii Preface

Summary: At the end of each chapter is a summary that serves as a concise

review of the key points described in detail throughout the chapter

Problems to Solve: These problems test a student’s ability to apply the

infor-mation covered in a particular chapter Detailed answers are provided in anappendix in the back of the book

Simbryo: New to this edition, Simbryo, located in the back of the book, is

an interactive CD-ROM that demonstrates normal embryologic events and theorigins of some birth defects This unique educational tool offers six originalvector art animation modules to illustrate the complex, three-dimensional as-pects of embryology Modules include normal early development as well ashead and neck, cardiovascular, gastrointestinal, genitourinary, and pulmonarysystem development

Connection Web Site: This student and instructor site (http://connection.

LWW.com/go/sadler) provides updates on new advances in the field and a labus designed for use with the book The syllabus contains objectives anddefinitions of key terms organized by chapters and the “bottom line,” whichprovides a synopsis of the most basic information that students should havemastered from their studies

syl-I hope you find this edition of Langman’s Medical Embryology to be an

excellent resource Together, the textbook, CD, and connection site provide auser-friendly and innovative approach to learning embryology and its clinicalrelevance

T W Sadler Twin Bridges, Montana

General Embryology

c h a p t e r 1

Gametogenesis: Conversion

of Germ Cells Into Male and

Female Gametes

Primordial Germ Cells

Development begins with fertilization, the

pro-cess by which the male gamete, the sperm, and the female gamete, the oocyte, unite to give rise to a zygote Gametes are derived from primordial germ cells (PGCs)

that are formed in the epiblast during the second weekand that move to the wall of the yolk sac (Fig 1.1) Duringthe fourth week these cells begin to migrate from the yolksac toward the developing gonads, where they arrive by theend of the fifth week Mitotic divisions increase their numberduring their migration and also when they arrive in the gonad

In preparation for fertilization, germ cells undergo gametogenesis,

which includes meiosis, to reduce the number of chromosomes and

cytodifferentiation to complete their maturation.

C L I N I C A L C O R R E L A T E

Primordial Germ Cells (PGCs) and Teratomas

Teratomas are tumors of disputed origin that often contain a variety

of tissues, such as bone, hair, muscle, gut epithelia, and others It isthought that these tumors arise from a pluripotent stem cell that candifferentiate into any of the three germ layers or their derivatives

3

4 Part One: General Embryology

Figure 1.1 An embryo at the end of the third week, showing the position of primordial

germ cells in the wall of the yolk sac, close to the attachment of the future umbilical cord From this location, these cells migrate to the developing gonad.

Some evidence suggests that PGCs that have strayed from their normal

mi-gratory paths could be responsible for some of these tumors Another source

is epiblast cells migrating through the primitive streak during gastrulation(see page 80)

The Chromosome Theory of Inheritance

Traits of a new individual are determined by specific genes on chromosomesinherited from the father and the mother Humans have approximately 35,000genes on 46 chromosomes Genes on the same chromosome tend to be inher-ited together and so are known as linked genes In somatic cells, chromosomes

appear as 23 homologous pairs to form the diploid number of 46 There are

22 pairs of matching chromosomes, the autosomes, and one pair of sex

chro-mosomes If the sex pair is XX, the individual is genetically female; if the pair is

XY, the individual is genetically male One chromosome of each pair is derived

from the maternal gamete, the oocyte, and one from the paternal gamete, the

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 5 sperm Thus each gamete contains a haploid number of 23 chromosomes, and

the union of the gametes at fertilization restores the diploid number of 46.

MITOSIS

Mitosis is the process whereby one cell divides, giving rise to two daughter

cells that are genetically identical to the parent cell (Fig 1.2) Each daughtercell receives the complete complement of 46 chromosomes Before a cell entersmitosis, each chromosome replicates its deoxyribonucleic acid (DNA) Duringthis replication phase the chromosomes are extremely long, they are spreaddiffusely through the nucleus, and they cannot be recognized with the light mi-croscope With the onset of mitosis the chromosomes begin to coil, contract,and condense; these events mark the beginning of prophase Each chromo-

some now consists of two parallel subunits, chromatids, that are joined at a narrow region common to both called the centromere Throughout prophase

the chromosomes continue to condense, shorten, and thicken (Fig 1.2 A),

but only at prometaphase do the chromatids become distinguishable

(Fig 1.2B ) During metaphase the chromosomes line up in the equatorial plane,

Figure 1.2 Various stages of mitosis In prophase, chromosomes are visible as

slen-der threads Doubled chromatids become clearly visible as individual units during

metaphase At no time during division do members of a chromosome pair unite Blue, paternal chromosomes; red, maternal chromosomes.

6 Part One: General Embryology

and their doubled structure is clearly visible (Fig 1.2C ) Each is attached by

microtubules extending from the centromere to the centriole, forming the totic spindle Soon the centromere of each chromosome divides, marking the

mi-beginning of anaphase, followed by migration of chromatids to opposite poles

of the spindle Finally, during telophase, chromosomes uncoil and lengthen,

the nuclear envelope reforms, and the cytoplasm divides (Fig 1.2, D and E ).

Each daughter cell receives half of all doubled chromosome material and thusmaintains the same number of chromosomes as the mother cell

MEIOSIS

Meiosis is the cell division that takes place in the germ cells to generate male

and female gametes, sperm and egg cells, respectively Meiosis requires two cell

divisions, meiosis I and meiosis II, to reduce the number of chromosomes to

the haploid number of 23 (Fig 1.3) As in mitosis, male and female germ cells

(spermatocytes and primary oocytes) at the beginning of meiosis I replicate

their DNA so that each of the 46 chromosomes is duplicated into sister

chro-matids In contrast to mitosis, however, homologous chromosomes then align themselves in pairs, a process called synapsis The pairing is exact and point

for point except for the XY combination Homologous pairs then separate intotwo daughter cells Shortly thereafter meiosis II separates sister chromatids.Each gamete then contains 23 chromosomes

Crossover

Crossovers, critical events in meiosis I, are the interchange of chromatid

seg-ments between paired homologous chromosomes (Fig 1.3C ) Segseg-ments of

chromatids break and are exchanged as homologous chromosomes separate

As separation occurs, points of interchange are temporarily united and form an

X-like structure, a chiasma (Fig 1.3C ) The approximately 30 to 40 crossovers

(one or two per chromosome) with each meiotic I division are most frequentbetween genes that are far apart on a chromosome

As a result of meiotic divisions, (a) genetic variability is enhanced through

crossover, which redistributes genetic material, and through random

distribu-tion of homologous chromosomes to the daughter cells; and (b) each germ cell

contains a haploid number of chromosomes, so that at fertilization the diploidnumber of 46 is restored

Polar Bodies

Also during meiosis one primary oocyte gives rise to four daughter cells, each

with 22 plus 1 X chromosomes (Fig 1.4 A) However, only one of these develops

into a mature gamete, the oocyte; the other three, the polar bodies, receive

little cytoplasm and degenerate during subsequent development Similarly, oneprimary spermatocyte gives rise to four daughter cells, two with 22 plus 1

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 7

Figure 1.3 First and second meiotic divisions A Homologous chromosomes approach

each other B Homologous chromosomes pair, and each member of the pair consists of two chromatids C Intimately paired homologous chromosomes interchange chromatid fragments (crossover) Note the chiasma D Double-structured chromosomes pull apart.

E Anaphase of the first meiotic division F and G During the second meiotic division,

the double-structured chromosomes split at the centromere At completion of division, chromosomes in each of the four daughter cells are different from each other.

X chromosomes and two with 22 plus 1 Y chromosomes (Fig 1.4B ) However,

in contrast to oocyte formation, all four develop into mature gametes

C L I N I C A L C O R R E L A T E S

Birth Defects and Spontaneous Abortions:

Chromosomal and Genetic Factors

Chromosomal abnormalities, which may be numerical or structural, are

important causes of birth defects and spontaneous abortions It is estimatedthat 50% of conceptions end in spontaneous abortion and that 50% of these

8 Part One: General Embryology

Figure 1.4 Events occurring during the first and second maturation divisions A The

primitive female germ cell (primary oocyte) produces only one mature gamete, the

ma-ture oocyte B The primitive male germ cell (primary spermatocyte) produces four

sper-matids, all of which develop into spermatozoa.

abortuses have major chromosomal abnormalities Thus approximately 25%

of conceptuses have a major chromosomal defect The most common mosomal abnormalities in abortuses are 45,X (Turner syndrome), triploidy,and trisomy 16 Chromosomal abnormalities account for 7% of major birth

chro-defects, and gene mutations account for an additional 8%.

Numerical Abnormalities

The normal human somatic cell contains 46 chromosomes; the normal

ga-mete contains 23 Normal somatic cells are diploid, or 2n; normal gaga-metes are haploid, or n Euploid refers to any exact multiple of n, e.g., diploid or

triploid Aneuploid refers to any chromosome number that is not euploid; it is usually applied when an extra chromosome is present (trisomy) or when one

is missing (monosomy) Abnormalities in chromosome number may nate during meiotic or mitotic divisions In meiosis, two members of a pair

origi-of homologous chromosomes normally separate during the first meiotic

divi-sion so that each daughter cell receives one member of each pair (Fig 1.5 A).

Sometimes, however, separation does not occur (nondisjunction), and both

members of a pair move into one cell (Fig 1.5, B and C ) As a result of

nondisjunction of the chromosomes, one cell receives 24 chromosomes,and the other receives 22 instead of the normal 23 When, at fertiliza-tion, a gamete having 23 chromosomes fuses with a gamete having 24 or

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 9

Figure 1.5 A Normal maturation divisions B Nondisjunction in the first meiotic

divi-sion C Nondisjunction in the second meiotic dividivi-sion.

22 chromosomes, the result is an individual with either 47 chromosomes(trisomy) or 45 chromosomes (monosomy) Nondisjunction, which occursduring either the first or the second meiotic division of the germ cells, mayinvolve the autosomes or sex chromosomes In women, the incidence ofchromosomal abnormalities, including nondisjunction, increases with age,especially at 35 years and older

Occasionally nondisjunction occurs during mitosis (mitotic

nondisjunc-tion) in an embryonic cell during the earliest cell divisions Such conditions

produce mosaicism, with some cells having an abnormal chromosome

num-ber and others being normal Affected individuals may exhibit few or many

of the characteristics of a particular syndrome, depending on the number ofcells involved and their distribution

Sometimes chromosomes break, and pieces of one chromosome attach

to another Such translocations may be balanced, in which case breakage and

reunion occur between two chromosomes but no critical genetic material is

lost and individuals are normal; or they may be unbalanced, in which case

part of one chromosome is lost and an altered phenotype is produced Forexample, unbalanced translocations between the long arms of chromosomes

14 and 21 during meiosis I or II produce gametes with an extra copy of mosome 21, one of the causes of Down syndrome (Fig 1.6) Translocations

chro-10 Part One: General Embryology

14

A

21 t(14;21)

Figure 1.6 A Translocation of the long arms of chromosomes 14 and 21 at the

cen-tromere Loss of the short arms is not clinically significant, and these individuals are clinically normal, although they are at risk for producing offspring with unbalanced

translocations B Karyotype of translocation of chromosome 21 onto 14, resulting in

Down syndrome.

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 11

Figure 1.7 Karyotype of trisomy 21 (arrow), Down syndrome.

are particularly common between chromosomes 13, 14, 15, 21, and 22 cause they cluster during meiosis

be-TRISOMY 21 (DOWN SYNDROME)

Down syndrome is usually caused by an extra copy of chromosome 21 somy 21, Fig 1.7) Features of children with Down syndrome include growth

(tri-retardation; varying degrees of mental (tri-retardation; craniofacial abnormalities,including upward slanting eyes, epicanthal folds (extra skin folds at the medialcorners of the eyes), flat facies, and small ears; cardiac defects; and hypotonia(Fig 1.8) These individuals also have relatively high incidences of leukemia,infections, thyroid dysfunction, and premature aging Furthermore, nearlyall develop signs of Alzheimer’s disease after age 35 In 95% of cases, thesyndrome is caused by trisomy 21 resulting from meiotic nondisjunction, and

in 75% of these instances, nondisjunction occurs during oocyte formation.The incidence of Down syndrome is approximately 1 in 2000 conceptusesfor women under age 25 This risk increases with maternal age to 1 in 300 atage 35 and 1 in 100 at age 40

In approximately 4% of cases of Down syndrome, there is an anced translocation between chromosome 21 and chromosome 13, 14, or 15(Fig 1.6) The final 1% are caused by mosaicism resulting from mitotic

unbal-12 Part One: General Embryology

Figure 1.8 A and B Children with Down syndrome, which is characterized by a flat,

broad face, oblique palpebral fissures, epicanthus, and furrowed lower lip C Another

characteristic of Down syndrome is a broad hand with single transverse or simian crease Many children with Down syndrome are mentally retarded and have congenital heart abnormalities.

nondisjunction These individuals have some cells with a normal some number and some that are aneuploid They may exhibit few or many

chromo-of the characteristics chromo-of Down syndrome

TRISOMY 18

Patients with trisomy 18 show the following features: mental retardation,

con-genital heart defects, low-set ears, and flexion of fingers and hands (Fig 1.9) Inaddition, patients frequently show micrognathia, renal anomalies, syndactyly,and malformations of the skeletal system The incidence of this condition isapproximately 1 in 5000 newborns Eighty-five percent are lost between 10weeks of gestation and term, whereas those born alive usually die by age

2 months

TRISOMY 13

The main abnormalities of trisomy 13 are mental retardation,

holo-prosencephaly, congenital heart defects, deafness, cleft lip and palate,and eye defects, such as microphthalmia, anophthalmia, and coloboma(Fig 1.10) The incidence of this abnormality is approximately 1 in 20,000live births, and over 90% of the infants die in the first month afterbirth

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 13

Figure 1.9 Photograph of child with trisomy 18 Note the prominent occiput, cleft lip,

micrognathia, low-set ears, and one or more flexed fingers.

Figure 1.10 A Child with trisomy 13 Note the cleft lip and palate, the sloping forehead,

and microphthalmia B The syndrome is commonly accompanied by polydactyly.

KLINEFELTER SYNDROME

The clinical features of Klinefelter syndrome, found only in males and usually

detected at puberty, are sterility, testicular atrophy, hyalinization of the niferous tubules, and usually gynecomastia The cells have 47 chromosomes

semi-with a sex chromosomal complement of the XXY type, and a sex chromatin

body (Barr body: formed by condensation of an inactivated sex

chromo-some; a Barr body is also present in normal females) is found in 80% of cases(Fig 1.11) The incidence is approximately 1 in 500 males Nondisjunction ofthe XX homologues is the most common causative event Occasionally, pa-tients with Klinefelter syndrome have 48 chromosomes: 44 autosomes andfour sex chromosomes (XXXY) Although mental retardation is not generally

14 Part One: General Embryology

Figure 1.11 Patient with Klinefelter syndrome showing normal phallus development

but gynecomastia (enlarged breasts).

part of the syndrome, the more X chromosomes there are, the more likelythere will be some degree of mental impairment

TURNER SYNDROME

Turner syndrome, with a 45,X karyotype, is the only monosomy

compat-ible with life Even then, 98% of all fetuses with the syndrome are neously aborted The few that survive are unmistakably female in appearance

sponta-(Fig 1.12) and are characterized by the absence of ovaries (gonadal

dysgen-esis) and short stature Other common associated abnormalities are webbed

neck, lymphedema of the extremities, skeletal deformities, and a broad chestwith widely spaced nipples Approximately 55% of affected women are mono-somic for the X and chromatin body negative because of nondisjunction In80% of these women, nondisjunction in the male gamete is the cause Inthe remainder of women, structural abnormalities of the X chromosome ormitotic nondisjunction resulting in mosaicism are the cause

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 15

Figure 1.12 Patient with Turner syndrome The main characteristics are webbed neck,

short stature, broad chest, and absence of sexual maturation.

TRIPLE X SYNDROME

Patients with triple X syndrome are infantite, with scanty menses and some

degree of mental retardation They have two sex chromatin bodies in theircells

Structural Abnormalities

Structural chromosome abnormalities, which involve one or more

chro-mosomes, usually result from chromosome breakage Breaks are caused byenvironmental factors, such as viruses, radiation, and drugs The result ofbreakage depends on what happens to the broken pieces In some cases, the

broken piece of a chromosome is lost, and the infant with partial deletion of

a chromosome is abnormal A well-known syndrome, caused by partial

dele-tion of the short arm of chromosome 5, is the cri-du-chat syndrome Such

children have a catlike cry, microcephaly, mental retardation, and congenitalheart disease Many other relatively rare syndromes are known to result from

a partial chromosome loss

Microdeletions, spanning only a few contiguous genes, may result in microdeletion syndrome or contiguous gene syndrome Sites where these

deletions occur, called contiguous gene complexes, can be identified by

high-resolution chromosome banding An example of a microdeletion

16 Part One: General Embryology

Figure 1.13 Patient with Angelman syndrome resulting from a microdeletion on

mater-nal chromosome 15 If the defect is inherited on the patermater-nal chromosome, Prader-Willi syndrome occurs (Fig 1.14).

occurs on the long arm of chromosome 15 (15q11–15q13) Inheriting the

deletion on the maternal chromosome results in Angelman syndrome, and

the children are mentally retarded, cannot speak, exhibit poor motor opment, and are prone to unprovoked and prolonged periods of laughter

devel-(Fig 1.13) If the defect is inherited on the paternal chromosome, Prader-Willi

syndrome is produced; affected individuals are characterized by hypotonia,

obesity, mental retardation, hypogonadism, and cryptorchidism (Fig 1.14).Characteristics that are differentially expressed depending upon whether thegenetic material is inherited from the mother or the father are examples of

genomic imprinting Other contiguous gene syndromes may be inherited

from either parent, including Miller-Dieker syndrome (lissencephaly,

devel-opmental delay, seizures, and cardiac and facial abnormalities resulting from a

deletion at 17p13) and most cases of velocardiofacial (Shprintzen) syndrome

(palatal defects, conotruncal heart defects, speech delay, learning disorders,and schizophrenia-like disorder resulting from a deletion in 22q11)

Fragile sites are regions of chromosomes that demonstrate a propensity

to separate or break under certain cell manipulations For example, fragilesites can be revealed by culturing lymphocytes in folate-deficient medium

Although numerous fragile sites have been defined and consist of CGG

re-peats, only the site on the long arm of the X chromosome (Xq27) has been

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 17

Figure 1.14 Patient with Prader-Willi syndrome resulting from a microdeletion on

pater-nal chromosome 15 If the defect is inherited on the materpater-nal chromosome, Angelman syndrome occurs (Fig 1.13).

correlated with an altered phenotype and is called the fragile X syndrome.

Fragile X syndrome is characterized by mental retardation, large ears, nent jaw, and pale blue irides Males are affected more often than females(1/1000 versus 1/2000), which may account for the preponderance of malesamong the mentally retarded Fragile X syndrome is second only to Downsyndrome as a cause of mental retardation because of chromosomal abnor-malities

promi-Gene Mutations

Many congenital formations in humans are inherited, and some show a clearmendelian pattern of inheritance Many birth defects are directly attributable

to a change in the structure or function of a single gene, hence the name single

gene mutation This type of defect is estimated to account for approximately

8% of all human malformations

18 Part One: General Embryology

With the exception of the X and Y chromosomes in the male, genes exist

as pairs, or alleles, so that there are two doses for each genetic determinant,

one from the mother and one from the father If a mutant gene produces anabnormality in a single dose, despite the presence of a normal allele, it is a

dominant mutation If both alleles must be abnormal (double dose) or if the

mutation is X-linked in the male, it is a recessive mutation Gradations in the

effects of mutant genes may be a result of modifying factors

The application of molecular biological techniques has increased ourknowledge of genes responsible for normal development In turn, geneticanalysis of human syndromes has shown that mutations in many of thesesame genes are responsible for some congenital abnormalities and childhooddiseases Thus, the link between key genes in development and their role inclinical syndromes is becoming clearer

In addition to causing congenital malformations, mutations can result in

inborn errors of metabolism These diseases, among which phenylketonuria,

homocystinuria, and galactosemia are the best known, are frequently panied by or cause various degrees of mental retardation

accom-Diagnostic Techniques for Identifying Genetic Abnormalities

Cytogenetic analysis is used to assess chromosome number and integrity.

The technique requires dividing cells, which usually means establishing cellcultures that are arrested in metaphase by chemical treatment Chromosomes

are stained with Giemsa stain to reveal light and dark banding patterns

(G-bands; Fig 1.6) unique for each chromosome Each band represents 5 to

10× 106base pairs of DNA, which may include a few to several hundred genes

Recently, high resolution metaphase banding techniques have been

devel-oped that demonstrate greater numbers of bands representing even smallerpieces of DNA, thereby facilitating diagnosis of small deletions

New molecular techniques, such as fluorescence in situ hybridization

(FISH), use specific DNA probes to identify ploidy for a few selected mosomes Fluorescent probes are hybridized to chromosomes or geneticloci using cells on a slide, and the results are visualized with a fluorescence

chro-microscope (Fig.1.15) Spectral karyotype analysis is a technique in which

every chromosome is hybridized to a unique fluorescent probe of a differentcolor Results are then analyzed by a computer

Morphological Changes During Maturation

of the Gametes

OOGENESIS

Maturation of Oocytes Begins Before Birth

Once primordial germ cells have arrived in the gonad of a genetic female, they

differentiate into oogonia (Fig 1.16, A and B ) These cells undergo a number

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 19

Figure 1.15 Fluorescence in situ hybridization (FISH) using a probe for chromosome

21 Two interphase cells and a metaphase spread of chromosomes are shown; each has three domains, indicated by the probe, characteristic of trisomy 21 (Down syndrome).

Figure 1.16 Differentiation of primordial germ cells into oogonia begins shortly after

their arrival in the ovary By the third month of development, some oogonia give rise

to primary oocytes that enter prophase of the first meiotic division This prophase may last 40 or more years and finishes only when the cell begins its final maturation During this period it carries 46 double-structured chromosomes.

20 Part One: General Embryology

4th month 7th month

Follicular cell

Resting primary oocyte (diplotene stage) Primary oocyte in

Figure 1.17 Segment of the ovary at different stages of development A Oogonia are

grouped in clusters in the cortical part of the ovary Some show mitosis; others have

differentiated into primary oocytes and entered prophase of the first meiotic division B.

Almost all oogonia are transformed into primary oocytes in prophase of the first meiotic

division C There are no oogonia Each primary oocyte is surrounded by a single layer

of follicular cells, forming the primordial follicle Oocytes have entered the diplotene stage of prophase, in which they remain until just before ovulation Only then do they enter metaphase of the first meiotic division.

of mitotic divisions and, by the end of the third month, are arranged in clusterssurrounded by a layer of flat epithelial cells (Fig 1.17 and 1.18) Whereas all

of the oogonia in one cluster are probably derived from a single cell, the flat

epithelial cells, known as follicular cells, originate from surface epithelium

covering the ovary

The majority of oogonia continue to divide by mitosis, but some of them

arrest their cell division in prophase of meiosis I and form primary oocytes

(Figs 1.16C and 1.17 A) During the next few months, oogonia increase rapidly

in number, and by the fifth month of prenatal development, the total number

of germ cells in the ovary reaches its maximum, estimated at 7 million At thistime, cell death begins, and many oogonia as well as primary oocytes becomeatretic By the seventh month, the majority of oogonia have degenerated exceptfor a few near the surface All surviving primary oocytes have entered prophase

of meiosis I, and most of them are individually surrounded by a layer of flat

epithelial cells (Fig 1.17B ) A primary oocyte, together with its surrounding flat

epithelial cells, is known as a primordial follicle (Fig 1.19 A).

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 21

Figure 1.18 A Primordial follicle consisting of a primary oocyte surrounded by a layer

of flattened epithelial cells B Early primary or preantral stage follicle recruited from

the pool of primordial follicles As the follicle grows, follicular cells become cuboidal and begin to secrete the zona pellucida, which is visible in irregular patches on the

surface of the oocyte C Mature primary (preantral) follicle with follicular cells forming

a stratified layer of granulosa cells around the oocyte and the presence of a well-defined zona pellucida.

Maturation of Oocytes Continues at Puberty

Near the time of birth, all primary oocytes have started prophase of meiosis I,

but instead of proceeding into metaphase, they enter the diplotene stage, a

resting stage during prophase that is characterized by a lacy network of

chro-matin (Fig 1.17C ) Primary oocytes remain in prophase and do not finish

their first meiotic division before puberty is reached, apparently because of oocyte maturation inhibitor (OMI), a substance secreted by follicular cells The

total number of primary oocytes at birth is estimated to vary from 700,000 to

2 million During childhood most oocytes become atretic; only approximately400,000 are present by the beginning of puberty, and fewer than 500 will beovulated Some oocytes that reach maturity late in life have been dormant inthe diplotene stage of the first meiotic division for 40 years or more beforeovulation Whether the diplotene stage is the most suitable phase to protectthe oocyte against environmental influences is unknown The fact that the risk

of having children with chromosomal abnormalities increases with maternalage indicates that primary oocytes are vulnerable to damage as they age

At puberty, a pool of growing follicles is established and continuously tained from the supply of primordial follicles Each month, 15 to 20 follicles

main-selected from this pool begin to mature, passing through three stages: 1)

pri-mary or preantral; 2) secondary or antral (also called vesicular or Graafian);

and 3) preovulatory The antral stage is the longest, whereas the preovulatory

stage encompasses approximately 37 hours before ovulation As the primaryoocyte begins to grow, surrounding follicular cells change from flat to cuboidal

and proliferate to produce a stratified epithelium of granulosa cells, and the unit

A F

Figure 1.19 A Secondary (antral) stage follicle The oocyte, surrounded by the zona

pellucida, is off-center; the antrum has developed by fluid accumulation between tercellular spaces Note the arrangement of cells of the theca interna and the theca

in-externa B Mature secondary (graafian) follicle The antrum has enlarged considerably,

is filled with follicular fluid, and is surrounded by a stratified layer of granulosa cells.

The oocyte is embedded in a mound of granulosa cells, the cumulus oophorus C

Pho-tomicrograph of a mature secondary follicle with an enlarged fluid-filled antrum (cavity,

Cav) and a diameter of 20 mm ( ×65) CO, cumulus oophorus; MG, granulosa cells; AF,

atretic follicle.

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 23

is called a primary follicle (Fig 1.18, B and C ) Granulosa cells rest on a

base-ment membrane separating them from surrounding stromal cells that form the

theca folliculi Also, granulosa cells and the oocyte secrete a layer of

glycopro-teins on the surface of the oocyte, forming the zona pellucida (Fig 1.18C ) As

follicles continue to grow, cells of the theca folliculi organize into an inner layer

of secretory cells, the theca interna, and an outer fibrous capsule, the theca

externa Also, small, finger-like processes of the follicular cells extend across

the zona pellucida and interdigitate with microvilli of the plasma membrane

of the oocyte These processes are important for transport of materials fromfollicular cells to the oocyte

As development continues, fluid-filled spaces appear between granulosa

cells Coalescence of these spaces forms the antrum, and the follicle is termed

a secondary (vesicular, Graafian) follicle Initially, the antrum is crescent

shaped, but with time, it enlarges (Fig 1.19) Granulosa cells surrounding the

oocyte remain intact and form the cumulus oophorus At maturity, the

sec-ondary follicle may be 25 mm or more in diameter It is surrounded by the

theca interna, which is composed of cells having characteristics of steroid cretion, rich in blood vessels, and the theca externa, which gradually mergeswith the ovarian stroma (Fig 1.19)

se-With each ovarian cycle, a number of follicles begin to develop, but ally only one reaches full maturity The others degenerate and become atretic

usu-(Fig 1.19C ) When the secondary follicle is mature, a surge in luteinizing

hormone (LH) induces the preovulatory growth phase Meiosis I is completed,

resulting in formation of two daughter cells of unequal size, each with 23

double-structured chromosomes (Fig 1.20, A and B ) One cell, the secondary oocyte,

receives most of the cytoplasm; the other, the first polar body, receives

prac-tically none The first polar body lies between the zona pellucida and the cell

Figure 1.20 Maturation of the oocyte A Primary oocyte showing the spindle of the

first meiotic division B Secondary oocyte and first polar body The nuclear membrane

is absent C Secondary oocyte showing the spindle of the second meiotic division The

first polar body is also dividing.

24 Part One: General Embryology

membrane of the secondary oocyte in the perivitelline space (Fig 1.20B ) The

cell then enters meiosis II but arrests in metaphase approximately 3 hoursbefore ovulation Meiosis II is completed only if the oocyte is fertilized; oth-erwise, the cell degenerates approximately 24 hours after ovulation The firstpolar body also undergoes a second division (Fig 1.20C)

SPERMATOGENESIS

Maturation of Sperm Begins at Puberty

Spermatogenesis, which begins at puberty, includes all of the events by which spermatogonia are transformed into spermatozoa At birth, germ cells in the

male can be recognized in the sex cords of the testis as large, pale cells

sur-rounded by supporting cells (Fig 1.21 A) Supporting cells, which are derived

from the surface epithelium of the gland in the same manner as follicular cells,

become sustentacular cells, or Sertoli cells (Fig 1.21C ).

Shortly before puberty, the sex cords acquire a lumen and become the

seminiferous tubules At about the same time, primordial germ cells give

rise to spermatogonial stem cells At regular intervals, cells emerge from this

stem cell population to form type A spermatogonia, and their production

marks the initiation of spermatogenesis Type A cells undergo a limited ber of mitotic divisions to form a clone of cells The last cell division pro-

num-duces type B spermatogonia, which then divide to form primary

sperma-tocytes (Figs 1.21 and 1.22) Primary spermasperma-tocytes then enter a prolonged

Figure 1.21 A Cross section through primitive sex cords of a newborn boy showing

primordial germ cells and supporting cells B and C Two segments of a seminiferous

tubule in transverse section Note the different stages of spermatogenesis.

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 25

Type A dark spermatogonia Type A pale spermatogonia Type A pale spermatogonia Type A pale spermatogonia Type A pale spermatogonia

Type B spermatogonia Primary spermatocytes

Secondary spermatocytes

Spermatids

Residual bodies Spermatozoa

Figure 1.22 Type A spermatogonia, derived from the spermatogonial stem cell

popu-lation, represent the first cells in the process of spermatogenesis Clones of cells are established and cytoplasmic bridges join cells in each succeeding division until individ- ual sperm are separated from residual bodies In fact, the number of individual inter- connected cells is considerably greater than depicted in this figure.

26 Part One: General Embryology

Type B

spermatogonium Spermatid

2nd meiotic division

Secondary spermatocyte

1st meiotic division

Resting primary spermatocyte

Mitotic

division

Figure 1.23 The products of meiosis during spermatogenesis in humans.

prophase (22 days) followed by rapid completion of meiosis I and formation

of secondary spermatocytes During the second meiotic division, these cells immediately begin to form haploid spermatids (Figs 1.21–1.23) Throughout

this series of events, from the time type A cells leave the stem cell tion to formation of spermatids, cytokinesis is incomplete, so that successivecell generations are joined by cytoplasmic bridges Thus, the progeny of a sin-gle type A spermatogonium form a clone of germ cells that maintain contactthroughout differentiation (Fig 1.22) Furthermore, spermatogonia and sper-matids remain embedded in deep recesses of Sertoli cells throughout theirdevelopment (Fig 1.24) In this manner, Sertoli cells support and protect thegerm cells, participate in their nutrition, and assist in the release of maturespermatozoa

popula-Spermatogenesis is regulated by luteinizing hormone (LH) production by

the pituitary LH binds to receptors on Leydig cells and stimulates testosteroneproduction, which in turn binds to Sertoli cells to promote spermatogenesis

Follicle stimulating hormone (FSH) is also essential because its binding to

Sertoli cells stimulates testicular fluid production and synthesis of intracellularandrogen receptor proteins

Spermiogenesis

The series of changes resulting in the transformation of spermatids into

sperma-tozoa is spermiogenesis These changes include (a) formation of the acrosome,

which covers half of the nuclear surface and contains enzymes to assist in etration of the egg and its surrounding layers during fertilization (Fig 1.25);

pen-(b) condensation of the nucleus; (c) formation of neck, middle piece, and tail; and (d) shedding of most of the cytoplasm In humans, the time required for

a spermatogonium to develop into a mature spermatozoon is approximately

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 27

Type A pale spermatogonia

Type B spermatogonia Type A dark spermatogonia

Peritubular cells Basal lamina

Junctional complex

Primary spermatocyte

Early spermatids

Late spermatids

Sertoli cell

Figure 1.24 Sertoli cells and maturing spermatocytes Spermatogonia, spermatocytes,

and early spermatids occupy depressions in basal aspects of the cell; late spermatids are in deep recesses near the apex.

C L I N I C A L C O R R E L A T E S

Abnormal Gametes

In humans and in most mammals, one ovarian follicle occasionally contains

two or three clearly distinguishable primary oocytes (Fig 1.26 A) Although

these oocytes may give rise to twins or triplets, they usually degenerate beforereaching maturity In rare cases, one primary oocyte contains two or even

three nuclei (Fig 1.26B ) Such binucleated or trinucleated oocytes die before

reaching maturity

In contrast to atypical oocytes, abnormal spermatozoa are seen quently, and up to 10% of all spermatozoa have observable defects Thehead or the tail may be abnormal; spermatozoa may be giants or dwarfs;

fre-and sometimes they are joined (Fig 1.26C ) Sperm with morphologic

abnor-malities lack normal motility and probably do not fertilize oocytes

28 Part One: General Embryology

Figure 1.25 Important stages in transformation of the human spermatid into the

sper-matozoon.

Figure 1.26 Abnormal germ cells A Primordial follicle with two oocytes B

Trinucle-ated oocyte C Various types of abnormal spermatozoa.

Summary

Primordial germ cells appear in the wall of the yolk sac in the fourth

week and migrate to the indifferent gonad (Fig 1.1), where they rive at the end of the fifth week In preparation for fertilization, both

ar-male and fear-male germ cells undergo gametogenesis, which includes

meio-sis and cytodifferentiation During meiomeio-sis I, homologous chromosomes pair and exchange genetic material; during meiosis II, cells fail to replicate

DNA, and each cell is thus provided with a haploid number of chromosomes

and half the amount of DNA of a normal somatic cell (Fig 1.3) Hence, ture male and female gametes have, respectively, 22 plus X or 22 plus Ychromosomes

ma-Birth defects may arise through abnormalities in chromosome number

or structure and from single gene mutations Approximately 7% of major

Chapter 1: Gametogenesis: Conversion of Germ Cells Into Male and Female Gametes 29

birth defects are a result of chromosome abnormalities, and 8%, are a

re-sult of gene mutations Trisomies (an extra chromosome) and monosomies

(loss of a chromosome) arise during mitosis or meiosis During meiosis, mologous chromosomes normally pair and then separate However, if sepa-

ho-ration fails (nondisjunction), one cell receives too many chromosomes and

one receives too few (Fig 1.5) The incidence of abnormalities of some number increases with age of the mother, particularly with mothersaged 35 years and older Structural abnormalities of chromosomes include

chromo-large deletions (cri-du-chat syndrome) and microdeletions Microdeletions involve contiguous genes that may result in defects such as Angelman syn-

drome (maternal deletion, chromosome 15q11–15q13) or Prader-Willi drome (paternal deletion, 15q11–15q13) Because these syndromes depend

syn-on whether the affected genetic material is inherited from the mother or the

father, they also are an example of imprinting Gene mutations may be

dom-inant (only one gene of an allelic pair has to be affected to produce an

al-teration) or recessive (both allelic gene pairs must be mutated) Mutations

re-sponsible for many birth defects affect genes involved in normal embryologicaldevelopment

In the female, maturation from primitive germ cell to mature gamete, which

is called oogenesis, begins before birth; in the male, it is called

spermatoge-nesis, and it begins at puberty In the female, primordial germ cells form oogonia After repeated mitotic divisions, some of these arrest in prophase of

meiosis I to form primary oocytes By the seventh month, nearly all

oogo-nia have become atretic, and only primary oocytes remain surrounded by

a layer of follicular cells derived from the surface epithelium of the ovary (Fig 1.17) Together, they form the primordial follicle At puberty, a pool of

growing follicles is recruited and maintained from the finite supply of dial follicles Thus, everyday 15 to 20 follicles begin to grow, and as they ma-

primor-ture, they pass through three stages: 1) primary or preantral; 2) secondary

or antral (vesicular, Graafian); and 3) preovulatory The primary oocyte

re-mains in prophase of the first meiotic division until the secondary follicle is

mature At this point, a surge in luteinizing hormone (LH) stimulates

pre-ovulatory growth: meiosis I is completed and a secondary oocyte and polarbody are formed Then, the secondary oocyte is arrested in metaphase ofmeiosis II approximately 3 hours before ovulation and will not complete thiscell division until fertilization In the male, primordial cells remain dormantuntil puberty, and only then do they differentiate into spermatogonia Thesestem cells give rise to primary spermatocytes, which through two successive

meiotic divisions produce four spermatids (Fig 1.4) Spermatids go through

a series of changes (spermiogenesis) (Fig 1.25) including (a) formation of

the acrosome, (b) condensation of the nucleus, (c) formation of neck, middle piece, and tail, and (d) shedding of most of the cytoplasm The time required

for a spermatogonium to become a mature spermatozoon is approximately

64 days

30 Part One: General Embryology

Problems to Solve

1 What is the most common cause of abnormal chromosome number? Give an

example of a clinical syndrome involving abnormal numbers of chromosomes.

2 In addition to numerical abnormalities, what types of chromosomal

alterations occur?

3 What is mosaicism, and how does it occur?

SUGGESTED READING

Chandley AC: Meiosis in man Trends Genet 4:79, 1988.

Clermont Y: Kinetics of spermatogenesis in mammals: seminiferous epithelium cycle and

sper-matogonial renewal Physiol Rev 52:198, 1972.

Eddy EM, Clark JM, Gong D, Fenderson BA: Origin and migration of primordial germ cells in

mammals Gamete Res 4:333, 1981.

Gelchrter TD, Collins FS: Principles of Medical Genetics Baltimore, Williams & Wilkins, 1990 Gorlin RJ, Cohen MM, Levin LS (eds): Syndromes of the Head and Neck 3rd ed New York, Oxford

Lenke RR, Levy HL: Maternal phenylketonuria and hyperphenylalaninemia: an international survey

of untreated and treated pregnancies N Engl J Med 303:1202, 1980.

Pelletier RA, We K, Balakier H: Development of membrane differentiations in the guinea pig

sper-matid during spermiogenesis Am J Anat 167:119, 1983.

Russell LD: Sertoligerm cell interactions: a review Gamete Res 3:179, 1980.

Stevenson RE, Hall JG, Goodman RM (eds): Human Malformations and Related Anomalies Vol I, II.

New York, Oxford University Press, 1993.

Thorogood P (ed): Embryos, Genes, and Birth Defects New York, Wiley, 1997.

Witschj E: Migration of the germ cells of the human embryos from the yolk sac to the primitive

gonadal folds Contrib Embryol 36:67, 1948.

c h a p t e r 2

First Week of Development: Ovulation to Implantation

Ovarian Cycle

At puberty, the female begins to undergo regular

monthly cycles These sexual cycles are controlled

by the hypothalamus Gonadotropin-releasing

hor-mone (GnRH) produced by the hypothalamus acts on

cells of the anterior pituitary gland, which in turn secrete

gonadotropins These hormones, follicle-stimulating hormone (FSH) and luteinizing hormone (LH), stimulate

and control cyclic changes in the ovary

At the beginning of each ovarian cycle, 15 to 20 primary(preantral) stage follicles are stimulated to grow under theinfluence of FSH (The hormone is not necessary to promotedevelopment of primordial follicles to the primary follicle stage,but without it, these primary follicles die and become atretic.) Thus,FSH rescues 15 to 20 of these cells from a pool of continuouslyforming primary follicles (Fig 2.1) Under normal conditions, onlyone of these follicles reaches full maturity, and only one oocyte isdischarged; the others degenerate and become atretic In the nextcycle, another group of primary follicles is recruited, and again, onlyone follicle reaches maturity Consequently, most follicles degeneratewithout ever reaching full maturity When a follicle becomes atretic,the oocyte and surrounding follicular cells degenerate and are replaced

by connective tissue, forming a corpus atreticum FSH also stimulates maturation of follicular (granulosa) cells surrounding the oocyte In

turn, proliferation of these cells is mediated by growth differentiation

31

32 Part One: General Embryology

Primary oocyte

Secondary follicle

Theca interna

Theca externa

Antrum

Primary follicle

Zona pellucida Granulosa

cells

Primordial follicle

Figure 2.1 From the pool of primordial follicles, every day some begin to grow and

de-velop into secondary (preantral) follicles, and this growth is independent of FSH Then,

as the cycle progresses, FSH secretion recruits primary follicles to begin development into secondary (antral, Graafian) follicles During the last few days of maturation of sec- ondary follicles, estrogens, produced by follicular and thecal cells, stimulate increased production of LH by the pituitary (Fig 2.13), and this hormone causes the follicle to enter the preovulatory stage, to complete meiosis I, and to enter meiosis II where it arrests in metaphase approximately 3 hours before ovulation.

factor-9 (GDF-9), a member of the transforming growth factor-β (TGF-β) family.

In cooperation, granulosa and thecal cells produce estrogens that (a) cause the

uterine endometrium to enter the follicular or proliferative phase; (b) cause

thinning of the cervical mucus to allow passage of sperm; and (c) stimulate the

pituitary gland to secrete LH At mid-cycle, there is an LH surge that (a)

ele-vates concentrations of maturation-promoting factor, causing oocytes to

com-plete meiosis I and initiate meiosis II; (b) stimulates production of progesterone

by follicular stromal cells (luteinization); and (c) causes follicular rupture and

ovulation

OVULATION

In the days immediately preceding ovulation, under the influence of FSH and

LH, the secondary follicle grows rapidly to a diameter of 25 mm Coincidentwith final development of the secondary follicle, there is an abrupt increase in

LH that causes the primary oocyte to complete meiosis I and the follicle to enterthe preovulatory stage Meiosis II is also initiated, but the oocyte is arrested inmetaphase approximately 3 hours before ovulation In the meantime, the sur-face of the ovary begins to bulge locally, and at the apex, an avascular spot, the

stigma, appears The high concentration of LH increases collagenase activity,

resulting in digestion of collagen fibers surrounding the follicle Prostaglandinlevels also increase in response to the LH surge and cause local muscular con-tractions in the ovarian wall Those contractions extrude the oocyte, whichtogether with its surrounding granulosa cells from the region of the cumulus

Chapter 2: First Week of Development: Ovulation to Implantation 33

Antrum

Theca interna

Luteal cells

Cumulus oophorus cells

Theca externa Ovarian stroma

1st polar body Granulosa cells

Oocyte in 2nd meiotic division

Corpus luteum Ovulation

Preovulatory follicle

Blood vessels

Fibrin

Figure 2.2 A Preovulatory follicle bulging at the ovarian surface B Ovulation The

oocyte, in metaphase of meiosis II, is discharged from the ovary together with a large number of cumulus oophorus cells Follicular cells remaining inside the collapsed folli-

cle differentiate into lutean cells C Corpus luteum Note the large size of the corpus

luteum, caused by hypertrophy and accumulation of lipid in granulosa and theca interna cells The remaining cavity of the follicle is filled with fibrin.

oophorus, breaks free (ovulation) and floats out of the ovary (Figs 2.2 and

2.3) Some of the cumulus oophorus cells then rearrange themselves around

the zona pellucida to form the corona radiata (Figs 2.4–2.6).

C L I N I C A L C O R R E L A T E S

Ovulation

During ovulation, some women feel a slight pain, known as middle pain

because it normally occurs near the middle of the menstrual cycle Ovulation

is also generally accompanied by a rise in basal temperature, which can bemonitored to aid in determining when release of the oocyte occurs Somewomen fail to ovulate because of a low concentration of gonadotropins Inthese cases, administration of an agent to stimulate gonadotropin release andhence ovulation can be employed Although such drugs are effective, theyoften produce multiple ovulations, so that the risk of multiple pregnancies is

10 times higher in these women than in the general population

CORPUS LUTEUM

After ovulation, granulosa cells remaining in the wall of the ruptured follicle,together with cells from the theca interna, are vascularized by surrounding ves-sels Under the influence of LH, these cells develop a yellowish pigment and

change into lutean cells, which form the corpus luteum and secrete the

mone progesterone (Fig 2.2C ) Progesterone, together with estrogenic

hor-mones, causes the uterine mucosa to enter the progestational or secretory

stage in preparation for implantation of the embryo.

34 Part One: General Embryology

Figure 2.3 A Scanning electron micrograph of ovulation in the mouse The surface

of the oocyte is covered by the zona pellucida The cumulus oophorus is composed of

granulosa cells B Scanning electron micrograph of a rabbit oocyte 1.5 hours after

ovulation The oocyte, which is surrounded by granulosa cells, lies on the surface of the ovary Note the site of ovulation.

Chapter 2: First Week of Development: Ovulation to Implantation 35

Figure 2.4 Relation of fimbriae and ovary Fimbriae collect the oocyte and sweep it into

the uterine tube.

OOCYTE TRANSPORT

Shortly before ovulation, fimbriae of the oviduct begin to sweep over the surface

of the ovary, and the tube itself begins to contract rhythmically It is thought thatthe oocyte surrounded by some granulosa cells (Figs 2.3 and 2.4) is carriedinto the tube by these sweeping movements of the fimbriae and by motion

of cilia on the epithelial lining Once in the tube, cumulus cells withdraw theircytoplasmic processes from the zona pellucida and lose contact with the oocyte.Once the oocyte is in the uterine tube, it is propelled by cilia with the rate

of transport regulated by the endocrine status during and after ovulation Inhumans, the fertilized oocyte reaches the uterine lumen in approximately 3 to

4 days

CORPUS ALBICANS

If fertilization does not occur, the corpus luteum reaches maximum ment approximately 9 days after ovulation It can easily be recognized as a yel-lowish projection on the surface of the ovary Subsequently, the corpus luteumshrinks because of degeneration of lutean cells and forms a mass of fibrotic

develop-36 Part One: General Embryology

A

B

Figure 2.5 A Scanning electron micrograph of sperm binding to the zona pellucida.

B The three phases of oocyte penetration In phase 1, spermatozoa pass through the

corona radiata barrier; in phase 2, one or more spermatozoa penetrate the zona cida; in phase 3, one spermatozoon penetrates the oocyte membrane while losing its

pellu-own plasma membrane Inset Normal spermatocyte with acrosomal head cap.